Cardiac Troponin in theEmergency Setting

Evangelos Giannitsis, MD, FESC

Assistant Professor

University of Heidelberg

Department of Cardiology, Angiology, and Pneumatology

no ST – Elevation

WorkingWorking--diagnosdiagnosisis

ECGECG

BioBio--chemistrychemistry

Final Final DxDxRiskRisk strat.strat.

SymptomSymptom

Acute Coronary Syndrome

ST – Elevation

STEMI NSTEMI Unstable Angina

Chest pain

cTroponins

-+

Thrombus

MicrovascularObstruction

Platelet-thrombin micro-emboliPlaque rupture

1st1st 2nd2nd 3rd3rd

CK-MBCK-MB

CK-MBCK-MBCK-MBCK-MB

Cutoff TnT CurveTnT Curve

embolus embolus embolus

Inflammation, spasm endothelial dysfunction

ACS ACS PathophysiologyPathophysiologyPlaque rupture, thrombosis and Plaque rupture, thrombosis and microembolizationmicroembolization

0 20 40 60 80

0

1

2

3

Myo (80 µg/L)

cTnT (0.1 µg/L)

cTnI (0.6 µg/L)

CKMB mass (7.5 µg/L)

hours after admission

mul

tiple

s of

upp

erre

fere

nce

limit

Sensitivity

- Microinfarction -

.01 .11

10 100

Low Risk High Risk

Troponins in Unstable Angina: MetaanalysisTroponins in Troponins in UnstableUnstable Angina: MetaanalysisAngina: Metaanalysis

Hamm,1992Wu, 1995Antman, 1996

Cin, 1996

Galvani, 1997

Solymoss, 1997

Luscher, 1997

Benamer, 1998

Olatidoye, 1998

Rebuzzi, 1998

Brisics, 1998

Hamm, 1999

11.71 (3.22,42.57)31.52 (6.89,144.19)3.82 (1.03,14.18)

17.91 (5.24,61.25)

6.55 (1.32,32.38)

4.93 (0.72,33.77)

5.93 (1.61, 21.79)

13.68 (3.87,48.33)

156.17 (17.39,1402.09)

25.27 (5.18,123.23)

7.96 (0.97,65.12)

5.48 (2.76,10.87)

9.39 (6.46,1367)

Ottani et al. Am Heart J, 2000

Total ��������

Death/ AMI 30 days

Risk Stratification Using New AMI Definition CutoffsGUSTO IV, FRISC II, TACTICS Results

0

2

4

6

TACTICS-TIMI-18FRISC-IIGUSTO-IV

5.9

2.4

0.8

5.1

1.6

2.6

TnT ≥≥≥≥0.03 TnT ≥≥≥≥ 0.02

deat

hat

30-

days

84098673015564552 2563

TnT ≥≥≥≥0.03N=

cutoff

P <0.001

P =0.002

P <0.01

TnT POS

TnT NEG

Okamatsu K et al, Circulation 2004

cTnT as Surrogate for Thrombus in ACS57 patients, NSTE-ACS, Angioscopy

Antithrombotic Treatment in cTnTPositive Unstable Angina

Lindahl et al,

JACC 1997

GpIIb/IIIa Inhibitors and positive Troponin T/I (High-Risk Patients)

6,6

10,8

13

17,319

13

0,7

2,94,3

5,7

11

12,9

0

2

4

6

8

10

12

14

16

18

20

Med PCI PRISM PRISM-PLUS PARAGON-B GUSTO-IV

Placebo

Gp2B/3a

% Death /MI 30-day FU

CAPTURE

3,1

10,6

2,8

5,3

0

5

10

15

TnT - TnT +

(%)

Troponin T: Death or MI at 30 Days

TnT cut point = 0.01 ng/ml (54% of Pts TnT +)

OR=0.47OR=0.47((0.29, 0.770.29, 0.77))

P=0.003P=0.003

p=NSp=NS

**CONS INV

N= 414 396 463 495

Early invasive vs conservative strategy

Mehta SR et al. JAMA. 2005;293:2908-17.

7 trials, N = 9212

*TIMI 3B, VANQWISH, MATE†FRISC II, TACTICS, VINO, RITA 3‡Data by troponin status available only in FRISC II, TACTICS, RITA 3

Invasive management of UA/NSTEMI meta-analysis: Subgroups

Trial Routine (%) Selective (%) Odds ratio

Favorsroutine

invasive

Favorsselective invasive P

<0.001

0.0010.42

0.010.40

0.92After 1999 † 12.49.4 0.73

Positive troponin ‡ 10.0 14.0 0.69Negative troponin 6.7 7.4 0.89

Marker positive 14.7 17.4 0.82

Marker negative 7.7 8.5 0.90

Before 1999* 19.3 19.6 0.99

0.001Overall 12.2 14.4 0.82

Odds ratio (95% Cl)0.5 1.0 2.0

Death or MI at follow-up

ISAR-REACT 2: Cumulative Incidence of Death, MI, or Urgent TVR in Subsets

With and Without Elevated Troponin Levels (>0.03 µg/L)

ISAR-REACT 2 = Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 2

Adapted with permission from Kastrati A, et al. JAMA. 2006;295:1531-1538.

20

15

10

5

0

0 5 10 15 20 25 30Days After Randomization

Cum

ulat

ive

Rat

e of

Prim

ary

End

Poi

nt, %

Placebo Group (N=1010)Abciximab Group (N=1012)

Troponin >0.03 µg/LLog-Rank P=.02

Troponin < 0.03 µg/LLog-Rank P=.98

Criteria of Myocardial Infarction

Detection of rise and/or fall of cardiacbiomarker(preferably troponins) with at least one valueabove the 99th percentile of the upperreference limit

With evidence of myocardial ischemia withat least one of the following:

• Symptoms of ischemia• New ST-T changes or LBBB• Development of new Q-waves• Imaging evidence of new loss of viablemyocardium• or new regional wall motion abnormality

0 %

3.1 %

5.8 %8.6 %

SubclassificationSubclassificationof Myocardial of Myocardial InfarctionInfarction

Type 1 Spontaneous myocardial infarction related to ischemia due to a primary coronary event such as plaque erosion or rupture, fissuring or dissection

Type 2 Myocardial infarction secondary to ischemia due to imbalance between oxygen demand and supply e.g. coronary spasm, anemia, or hypotension

Type 3 Sudden cardiac death with symptoms of ischemia, accompanied by new ST elevation or LBBB, or verified coronary thrombus by angiography or autopsy, but death occurring before blood samples could be obtained

Type 4a Myocardial infarction associated with PCI

Type 4b Myocardial infarction associated with verified stent thrombosis

Type 5 Myocardial infarction associated with CABG

� Cardiac contusion, including ablation, pacing, cardio version, or endomyocardial biopsy

� Congestive heart failure – acute and chronic

� Aortic dissection, aortic valve disease, or hypertrophi c cardiomyopathy

� Tachy- or bradyarrhythmia, or heart block,

� Apical ballooning syndrome

� Rhabdomyolysis with cardiac injury

� Pulmonary embolism, severe pulmonary hypertension

� Renal failure

� Acute neurological disease including stroke, or subarach noidal hemorrhage

� Infiltrative diseases, e.g. amyloidosis, hemochrmato sis, sarcoidosis and scleroderma

� Inflammatory diseases, e.g. myocarditis, or myocardia l extension of endo/pericarditis

� Drug toxicity, e.g.adriamycin, 5-fluorouracil, herc eptin, snake venom

� Critically ill patients, especially with respiratory fai lure, or sepsis

� Burns, especially if affecting > 30 % of body surface ar ea

Elevations of Troponin in the Absence of an Acute Coronary Syndrome

0 5 10 15 20 25 300

0.2

0.4

0.6

0.8

1

cTnT < 0.1 ng/ml

cTnT > 0.1 ng/ml

log rank 17.05, p < 0.001

follow up (days)

cum

ulat

ive

surv

ival

[%]

Non AMI Release of Cardiac Markers:Pulmonary Embolism

Giannitsis et al, Circulation2000

False-Positive Troponin Result

� Rhabdomyolysis in 1st and 2nd generationtroponin assays

� Heterophilic antibodies

� Rheumatoid factor

� Fibrin clots

� Microparticles

� Analyser or analyte malfunction

cTnT in renal failureand ESRD

early (< 72 hrs)

Invasive management

• Elevated troponin levels• Dynamic ST or T wave changes (symptomatic or silent)• Diabetes mellitus• Renal dysfunction (GFR<60ml/min/1.73m² ) • Reduced left ventricular function (EF <40%) • Early post-infarction angina• PCI within 6 months• Prior CABG• Intermediate to high GRACE risk score

ESC Guidelines 2007 NSTE-ACS

Relation Between Creatinine Clearance,Troponin, and Outcomes

Troponin T LevelTroponin T Level(mcg per Liter)(mcg per Liter)

Creatinine ClearanceCreatinine Clearance(ml per minute)(ml per minute)

0.000-0.0100.000-0.010

0.011-0.1140.011-0.114

0.015-0.4630.015-0.463

0.465-17.300.465-17.30 > 98.6> 98.677.0-98.577.0-98.5

58.4-76.958.4-76.94.7-58.34.7-58.3

Death or MI %Death or MI %2525

2020

1515

1010

55

00

2525

2020

1515

1010

55

00

The GUSTO-IV Trial

Cardiac Troponin T and Renal Failure

Multiples of ReferenceRangecTnT = 0.1 ng/mlcTnI = 2.0 ng/ml

Chronic Renal FailureSkeletal Trauma

cTnT cTnI cTnT cTnI

0.1

0.2

0.5

1.0

20.0

100.0

Wu A. et al, Ann. Clin. Lab. Sci. 26 (1996)

Apple F et al, Circulation 2002

cTnT cTnI (Dade-Behring Dimension)

cTnT vs cTnI in End-Stage Renal Disease:Predictive Value

Percent positive at: 99th percentile 82 % vs 6 %10 % CV 53 % vs 1 %ROC 20 % vs 0.4 %

Khan NA, et alCirculation 2005

Troponin T and All-cause Mortality in ESRD - A Meta-analysis

Overall

� elevated cardiac troponins indicate myocardial necosis

� allow classification of ACS, risk stratification, guidance of therapy

� knowledge of the new universal definition of MI important

� must consider differential diagnoses of elevated troponinin the absence of ACS

�elevated troponin in the absence of ACS associated withadverse prognosis – the reason should be persued !

�in renal failure prognostic information of cTn in symptomatic patients with suspected ACS is maintained

� in asymptomatic ESRD cTnT is helpful as a complementarytool for prognostication

Elecsys® high sensitive Troponin TInter-Device Precision 2010 STAT

8 devices; 1 Run

Tropomyosin

T TII

I IT

C

CC

Structurally boundActin

I

C

C

T

T

T

T

T

TC

C

C

C

Cytosolic free pool

II I

I

Cardiac myocyte

TI C

I C

T

Invasive vs. Non-invasive strategy in relation to NT-proBNP

-FRISC II-

days

7206004803602401200

12

10

8

6

4

2

days

7206004803602401200

25

20

15

10

5

3rd tertile+Non-inv

3rd tertile+Inv

1st or 2nd tertile+Non-inv

1st or 2nd tertile+Inv

3rd+Noninv

3rd+Inv

1-2nd+Noninv

1-2nd+Inv

Death Death or MI

P=0.11

% %

Jernberg et al. AHA -02

3,1

10,6

2,8

5,3

0

5

10

15

TnT - TnT +

(%)

Troponin T: Death or MI at 30 Days

TnT cut point = 0.01 ng/ml (54% of Pts TnT +)

OR=0.47OR=0.47((0.29, 0.770.29, 0.77))

P=0.003P=0.003

p=NSp=NS

**CONS INV

N= 414 396 463 495

Early invasive vs conservative strategy